Non-criteria antiphospholipid antibodies and calprotectin as potential biomarkers in pediatric antiphospholipid syndrome.

Our study aimed to evaluate the presence, clinical associations, and potential mechanistic roles of non-criteria antiphospholipid antibodies (aPL) and circulating calprotectin, a highly stable marker of neutrophil extracellular trap release (NETosis), in pediatric APS patients. We found that 79% of pediatric APS patients had at least one non-criteria aPL at moderate-to-high titer. Univariate logistic regression demonstrated that positive anti-beta-2 glycoprotein I domain 1 (anti-D1) IgG (p = 0.008), anti-phosphatidylserine/prothrombin (aPS/PT) IgG (p < 0.001), and aPS/PT IgM (p < 0.001) were significantly associated with venous thrombosis. Positive anti-D1 IgG (p < 0.001), aPS/PT IgG (p < 0.001), and aPS/PT IgM (p = 0.001) were also associated with non-thrombotic manifestations of APS, such as thrombocytopenia. Increased levels of calprotectin were detected in children with APS. Calprotectin correlated positively with absolute neutrophil count (r = 0.63, p = 0.008) and negatively with platelet count (r = -0.59, p = 0.015). Mechanistically, plasma from pediatric APS patients with high calprotectin levels impaired platelet viability in a dose-dependent manner.

Updates in childhood Sjogren's syndrome.

PURPOSE OF REVIEW: Childhood Sjogren's syndrome (cSS) is a rare, chronic autoimmune disease characterized by inflammation of the exocrine glands. cSS is underrecognized because of differences in clinical presentation compared with adults. Until recently, publications describing clinical manifestations in cSS were limited to case reports and case series with small numbers of patients. Diagnostic studies to assess glandular symptoms in adults, are less commonly obtained in children. RECENT FINDINGS: Recent cohort studies describe presenting diagnostic clinical features in large populations of cSS and demonstrate how current classification criteria, used in adults, are not applicable to children. Recurrent parotitis is the consistent predominant manifestation that is inversely correlated with age. Novel salivary biomarkers and salivary gland ultrasonography are important objective measure, which may improve diagnosis and disease monitoring. Standardized treatment recommendations are needed. SUMMARY: Findings from large cohort studies provide a framework for the future development of diagnostic criteria for cSS. Such criteria should incorporate objective measures that are easily obtained in children. Future research to improve understanding of the application of novel biomarkers and imaging and developing consensus on treatment recommendations is needed.

Paediatric systemic lupus erythematosus: insights from translational research.

Investigations in paediatric SLE contributed significantly to the discovery of the association of type I IFNs with lupus and underscored the potential application of this knowledge by informing the use of glucocorticoid therapy. Recent, promising research reveals biomarkers that may yield more focused clinical monitoring and assessment of response to treatment. This article reviews unique features of paediatric SLE and details important developments in paediatric lupus research.

Development and Validation of a Juvenile Spondyloarthritis Disease Flare Measure: Ascertaining Flare in Patients With Inactive Disease.

OBJECTIVE: Our objective was to develop and validate a composite disease flare definition for juvenile spondyloarthritis (SpA) that would closely approximate the clinical decision made to reinitiate or not reinitiate systemic therapy after therapy de-escalation. METHODS: Retrospective chart reviews of children with SpA who underwent systemic therapy de-escalation of biologic or conventional disease-modifying antirheumatic drugs were used to develop and validate the flare outcome. Data on independent cohorts for development (1 center) and validation (4 centers) were collected from large tertiary health care systems. Core measure thresholds and candidate disease flare outcomes were assessed using sensitivity, specificity, positive predictive values (PPVs) and negative predictive values (NPVs), and the receiver operating characteristic (ROC) area under the curve (AUC), with physician assessment of active disease plus re-initiation of standard dose of systemic therapy as the reference standard. RESULTS: Of the candidate definitions, clinically meaningful worsening in ≥3 of the following 5 core measures performed best: caregiver/patient assessment of well-being; physician assessment of disease activity; caregiver/patient assessment of pain, physical function, and active joint count. The ROC AUC was 0.91, PPV 87.5%, NPV 98.1%, sensitivity 82.4%, and specificity 98.7%. Cronbach's α was 0.81, signifying internal consistency, and factor analysis demonstrated that the outcome measured 1 construct. The Juvenile SpA Flare measure had face validity according to 21 surveyed pediatric rheumatologists. Juvenile SpA Flare had an ROC AUC of 0.85, a PPV of 92.3%, and an NPV of 96.8% in the validation cohort. CONCLUSION: There is initial support for the validity of the Juvenile SpA Flare measure as a tool to identify disease flare in juvenile SpA patients de-escalating therapy, and the measure is potentially applicable in clinical practice, observational studies, and therapeutic trials.

Correction: Stoll et al. Impact of HLA-B27 and Disease Status on the Gut Microbiome of the Offspring of Ankylosing Spondylitis Patients. Children 2022, 9, 569.

The authors wish to make the following correction to this paper [...].

Impact of HLA-B27 and Disease Status on the Gut Microbiome of the Offspring of Ankylosing Spondylitis Patients.

Multiple studies have shown the microbiota to be abnormal in patients with spondyloarthritis (SpA). The purpose of this study was to explore the genetic contributions of these microbiota abnormalities. We analyzed the impact of HLA-B27 on the microbiota of children at risk for SpA and compared the microbiota of HLA-B27+ pediatric offspring of ankylosing spondylitis (AS) patients with that of HLA-B27+ children with SpA. Human DNA was obtained from the offspring for determination of HLA-B27 status and polygenic risk score (PRS). Fecal specimens were collected from both groups for sequencing of the V4 region of the 16S ribosomal RNA gene. Among the offspring of AS patients, there was slight clustering by HLA-B27 status. After adjusting for multiple comparisons, five operational taxonomic units (OTUs) representing three unique taxa distinguished the HLA-B27+ from negative children: Blautia and Coprococcus were lower in the HLA-B27+ offspring, while Faecalibacterium prausnitzii was higher. HLA-B27+ offspring without arthritis were compared to children with treatment-naïve HLA-B27+ SpA. After adjustments, clustering by diagnosis was present. A total of 21 OTUs were significantly associated with diagnosis state, including Bacteroides (higher in SpA patients) and F. prausnitzii (higher in controls). Thus, our data confirmed associations with B. fragilis and F. prausnitzii with juvenile SpA, and also suggest that the mechanism by which HLA-B27 is associated with SpA may not involve alterations of the microbiota.

Hypovitaminosis D is associated with greater body mass index and disease activity in pediatric systemic lupus erythematosus.

OBJECTIVES: To determine whether pediatric systemic lupus erythematosus (SLE) is associated with alterations in the vitamin D-parathyroid hormone (PTH) axis and to assess the relation between vitamin D deficiency and SLE activity. STUDY DESIGN: 25-hydroxy vitamin D [25(OH)D], 1,25-dihydroxy vitamin D [1,25(OH)2D], and intact PTH were measured in subjects with SLE (n = 38) and healthy controls (n = 207), ages 5 to 21 years. Vitamin D status and its relation with disease activity were assessed using multivariable logistic and linear regression. RESULTS: Severe vitamin D deficiency (25(OH)D <10 ng/ml) was observed in a significantly higher proportion of subjects with SLE (36.8% vs 9.2%, P < .001). In SLE, the odds ratio (OR) for severe deficiency was 2.37 (P = .09), adjusting for age, sex, race, and season. However, for each 1 SD greater body mass index (BMI) z-score, 25(OH)D levels were 4.2 ng/mL lower (P = .01) in SLE, compared with controls. Adjusting for 25(OH)D levels, SLE was associated with significantly lower 1,25(OH)2D (P < .001) and intact PTH levels (P = .03). Greater SLE disease activity index scores were observed in those with 25(OH)D <20 ng/mL (P = .01). CONCLUSIONS: SLE was associated with vitamin D deficiency, particularly among those subjects with SLE who were overweight. Future studies should assess the effect of vitamin D supplementation on skeletal and nonskeletal outcomes in SLE.

Comparative Effectiveness of Tumor Necrosis Factor Agents and Disease-modifying Antirheumatic Therapy in Children with Enthesitis-related Arthritis: The First Year after Diagnosis.

OBJECTIVE: To characterize the effect of anti-tumor necrosis factor (TNF) therapy compared to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in children with enthesitis-related arthritis (ERA) over the first year after diagnosis. METHODS: We conducted a multicenter retrospective comparative effectiveness study of children diagnosed with ERA. We estimated the effect of anti-TNF therapy on clinical variables (active joint count, tender entheses count) and patient-reported pain and global assessment of disease activity over the first year after diagnosis using state-of-the-art comparative effectiveness analytic methods. RESULTS: During the study period, 217 patients newly diagnosed with ERA had a total of 965 clinic visits the first year after disease diagnosis. Children [median age 11.6 yrs, interquartile range 10-14] were treated with anti-TNF monotherapy (n = 33, 15.2%), csDMARD monotherapy (n = 73, 33.6%), or both (n = 52, 23.9%) in the first year after disease diagnosis. There was a statistically significant improvement in the primary outcome, active joint count, over time in children who received an anti-TNF drug versus those who did not (p = 0.03). Additionally, use of anti-TNF therapy versus no anti-TNF therapy was associated with less patient-reported pain (p < 0.01) and improved disease activity over time as assessed by the clinical Juvenile Arthritis Disease Activity Score (p < 0.01). The magnitude of estimated effect on clinical outcomes was uniformly greater, with the exception of tender entheses count, in children treated with an anti-TNF drug versus a csDMARD. CONCLUSION: During the first year after diagnosis, anti-TNF exposure was associated with benefits for several clinically meaningful outcomes in children with enthesitis-related arthritis.

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis.

BACKGROUND: To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy. METHODS: Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months. RESULTS: The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF. CONCLUSIONS: Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.

Multicenter inception cohort of enthesitis-related arthritis: variation in disease characteristics and treatment approaches.

BACKGROUND: Enthesitis-related arthritis (ERA) is a specific subtype of juvenile idiopathic arthritis (JIA) defined according to the International League of Associations for Rheumatology (ILAR) criteria. We aimed to characterize the clinical features and treatment regimens in an inception cohort of children with ERA. METHODS: We performed a retrospective, cross-sectional, multicenter cohort study including subjects diagnosed with ERA between 1989 and 2012. Patients all fulfilled the ILAR criteria for ERA within 3 months of initial presentation to the rheumatology clinic. Differences in the prevalence of clinical criteria across study sites and by human leukocyte antigen (HLA)-B27 status were assessed using the Wilcoxon rank-sum or chi-square test, as appropriate. RESULTS: Two hundred thirty-four children met the inclusion criteria. Their median age at diagnosis was 11.6 years, and 59% were HLA-B27-positive. Sixty-nine percent had enthesitis and arthritis at the time of diagnosis. Seventy-eight percent had a pauciarticular onset. The prevalence of all ILAR criteria at diagnosis, except arthritis and acute anterior uveitis, differed significantly across sites (all p < 0.01). Medication use varied significantly across sites for children with peripheral arthritis (p < 0.001), but not for sacroiliitis or enthesitis only. Nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs were the most commonly prescribed treatments, with anti-TNF agents primarily being initiation for sacroiliitis. HLA-B27 positivity was associated with male sex, higher active joint count, sacroiliitis, and higher disease activity at disease onset. CONCLUSIONS: The majority of children had a pauciarticular onset, and several statistically significant clinical differences based on HLA-B27 status were identified. The observed heterogeneity in clinical presentation across sites reflects either true differences in patient populations or differences in how the ILAR criteria are being applied.

Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults.

OBJECTIVE: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined. RESULTS: The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.

Development and retrospective validation of the juvenile spondyloarthritis disease activity index.

OBJECTIVE: To develop and validate the Juvenile Spondyloarthritis Disease Activity Index (JSpADA) for use in clinical practice and research. METHODS: Using modified Delphi consensus techniques, 10 items were selected by participants in the international pediatric rheumatology listserv, the Childhood Arthritis and Rheumatology Research Alliance, and the listserv for the pediatric section of the American College of Rheumatology. Validation was performed in a retrospective multicenter cohort of 244 children. RESULTS: In total, 106 physicians representing 14 countries completed the initial questionnaire. Completion rates for the subsequent questionnaires were 84%, 75%, and 77% of the original respondents. Ten items exceeded 80% consensus: arthritis, enthesitis, patient pain assessment, inflammatory markers, morning stiffness, clinical sacroiliitis, uveitis, back mobility, and patient and physician assessments of disease activity. After item analysis, 2 items were eliminated (patient and physician assessments of disease activity). Factor analysis identified 3 primary domains that explained 58% of the variance: peripheral disease, axial disease, and uveitis. The Cronbach's α coefficient was 0.66. The JSpADA had high or moderate correlations with the Juvenile Arthritis Disease Activity Score (r = 0.81), patient and physician assessments of disease activity (r = 0.70 and r = 0.66, respectively), and the Childhood Health Assessment Questionnaire (r = 0.56). The JSpADA discriminated well between subjects with active versus inactive disease (P < 0.001) and was responsive to improvement or worsening in disease activity over time (P < 0.001). CONCLUSION: Using international input and consensus formation techniques, we developed and validated the first disease activity assessment for juvenile spondyloarthritis. Future studies should validate the JSpADA in a prospective multicenter cohort.